Pesta Dominik, Anadol-Schmitz Evrim, Sarabhai Theresia, Op den Kamp Yvo, Gancheva Sofiya, Trinks Nina, Zaharia Oana-Patricia, Mastrototaro Lucia, Lyu Kun, Habets Ivo, Op den Kamp-Bruls Yvonne M H, Dewidar Bedair, Weiss Jürgen, Schrauwen-Hinderling Vera, Zhang Dongyan, Gaspar Rafael Calais, Strassburger Klaus, Kupriyanova Yuliya, Al-Hasani Hadi, Szendroedi Julia, Schrauwen Patrick, Phielix Esther, Shulman Gerald I, Roden Michael
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany.
German Center for Diabetes Research (DZD), Partner Düsseldorf, Düsseldorf, Germany.
Sci Adv. 2025 Jan 3;11(1):eadr8849. doi: 10.1126/sciadv.adr8849. Epub 2025 Jan 1.
The athlete's paradox states that intramyocellular triglyceride accumulation associates with insulin resistance in sedentary but not in endurance-trained humans. Underlying mechanisms and the role of muscle lipid distribution and composition on glucose metabolism remain unclear. We compared highly trained athletes (ATHL) with sedentary normal weight (LEAN) and overweight-to-obese (OVWE) male and female individuals. This observational study found that ATHL show higher insulin sensitivity, muscle mitochondrial content, and capacity, but lower activation of novel protein kinase C (nPKC) isoforms, despite higher diacylglycerol concentrations. Notably, sedentary but insulin sensitive OVWE feature lower plasma membrane-to-mitochondria -1,2-diacylglycerol ratios. In ATHL, calpain-2, which cleaves nPKC, negatively associates with PKCε activation and positively with insulin sensitivity along with higher GLUT4 and hexokinase II content. These findings contribute to explaining the athletes' paradox by demonstrating lower nPKC activation, increased calpain, and mitochondrial partitioning of bioactive diacylglycerols, the latter further identifying an obesity subtype with increased insulin sensitivity (NCT03314714).
运动员悖论指出，在久坐不动的人群中，肌细胞内甘油三酯的积累与胰岛素抵抗相关，而在耐力训练的人群中则不然。其潜在机制以及肌肉脂质分布和组成对葡萄糖代谢的作用仍不清楚。我们将训练有素的运动员（ATHL）与久坐不动的正常体重（LEAN）以及超重至肥胖（OVWE）的男性和女性个体进行了比较。这项观察性研究发现，尽管二酰基甘油浓度较高，但ATHL表现出更高的胰岛素敏感性、肌肉线粒体含量和能力，以及新型蛋白激酶C（nPKC）亚型的较低激活。值得注意的是，久坐不动但胰岛素敏感的OVWE的质膜与线粒体-1,2-二酰基甘油比率较低。在ATHL中，切割nPKC的钙蛋白酶-2与PKCε激活呈负相关，与胰岛素敏感性呈正相关，同时GLUT4和己糖激酶II含量较高。这些发现通过证明较低的nPKC激活、钙蛋白酶增加以及生物活性二酰基甘油的线粒体分配，有助于解释运动员悖论，后者进一步确定了一种胰岛素敏感性增加的肥胖亚型（NCT03314714）。
